Certain substituted 1-amino-1,2,3,4-tetrahydro naphthalenes and pharmaceutically acceptable salts thereof



United States Patent 3,534,055 CERTAIN SUBSTITUTED1-AMlN0-1,2,3,4-TETRA- HYDRO NAPHTHALENES AND PHARMACEU- TICALLYACCEPTABLE SALTS THEREOF Maurice Ward Gittos, Slough, John William JamesLangley, and Leslie Frederick Wiggins, Wargrave, England, -assignors toAspro-Nicholas Limited, London, England, a limited company of GreatBritain No Drawing. Continuation of abandoned application Ser.

No. 652,029, July 10, 1967, which is a continuafion-inpart ofapplication Ser. No. 623,470, Mar. 15, 1967, which in turn is acontinuation of abandoned application Ser. No. 385,761, July 28, 1964.This application Aug. 18, 1969, Ser. No. 855,794 Claims priority,application Great Britain, July 16, 1966, 32,067/ 66 Int. Cl. C07c87/66, 91/16 U.S. Cl. 260-295 Claims ABSTRACT OF TIE DISCLOSURE A numberof N-cyclopropyl-l-aminoindanes and-lamino-l,2,3,4-tetrahydronaphthalenes are disclosed. They have usefulpharmacological properties in that, when administered to hypertensiveanimals, including humans, they lower the blood pressure of theseanimals. Pharmaceutical compositions containing these compounds may beadministered orally, rectally or parenterally in dosage unit form, eachdosage unit containing from 1 to 150 mg. of active ingredient. Up to 2or 3 dosage units may be administered 4 times daily. Reduced dosages maybe used for maintenance therapy.

CROSS REFERENCE TO RELATED APPLICATIONS This application is acontinuation of application Ser. No. 652,029 filed July 10, 1967, nowabandoned, which in turn is a continuation-in-part of application Ser,No. 623,470 filed Mar. 15, 1967, which in turn is a continuation of Ser.No. 385,761 filed July 28, 1964, now abandoned.

This invention relates to benzocycloalkane compounds and in particularto methods of treatment involving the administration of said compounds.

It has been found in accordance with the present invention that certainN-substituted l-aminobenzocycloalkane compounds are useful in thetreatment of hypertension in animals, including humans, in that theycause a pronounced lowering of blood pressure.

These aminobenzocycloalkane compounds are represented by the generalformula:

N-Ra R1 and the pharmaceutically acceptable salts thereof, wherein R andR which may be the same or different, are hydrogen, methyl, ethyl,halogen, for example, chlorine, bromine and fluorine, hydroxy or loweralkoxy; R is hydrogen, lower alkyl or cyclopropyl; R is cyclopropyl; andY is methylene or ethylene.

The terms lower alkyl and lower alkoxy are used in this specification asmeaning respectively alkyl and alkoxy groups containing from 1 to 4carbon atoms, for example, methyl, ethyl, propyl, isopropyl, bntyl,t.-butyl, methoxy, ethoxy, isopropoxy, butoxy, s.-butoxy and t.-butoxy.

Within the group of compounds encompassed by Formula I, there is apharmaceutically preferred group of 3,534,055 Patented Oct. 13, 1970compounds in which R is hydrogen or cyclopropyl and/ or R and R areother than hydrogen.

Specific compounds which may be used in accordance with the method ofthe present invention include N-cyclopropyl-l-aminoindaneN-methyl-N-cyclopropyl-l-arninoindaneIL-ethyl-N-cyclopropyl-l-aminoindaneN-isopropyl-N-cyclopropyl-l-aminoindaneN-t.-butyl-N-cyclopropyl-l-aminoindaneN-cyclopropyl-S-methoxy-l-aminoindaneN-cyclopropyl-S,7-dimethoxy-l-aminoindaneN,N-dicyclopropyl-6-ethoxy-l-aminoindaneN,N-dicyclopropyl-4-but0xy-l-aminindaneN-cyclopropyl-6-methyl-l-aminoindane N-cyclopropyl-7-ethyl-l-aminoindaneN-ethyl-N-cyclopropyl-6,7-dimethyl-l-aminoindaneN-methyl-N-cyclopropyl-S -hydroxy-1-aminoindaneN-cyclopropyl-6-hydroxy-l-aminoindaneN-cyclopropyl-S-chloro-l-aminoindane N-cyclopropyl-S,6-dibromo-1-aminoindane N-cyclopropyl-7-fluoro-l-aminoindaneN-butyl-N-cyclopropyl-S-chloro-7-methoxy-laminoindaneN-cyclopropyl-4-methyl-6-bromo-l-aminoindaneN-cyclopropyl-l-amino-l,2,3,4-tetrahydronaphthaleneN,N-dicyclopropyl-l-amino-l,2,3,4-tetrahydro naphthaleneN,N-dicyclopropyl-S-ethoxy-l-amino-l,2,3,4-

tetrahydronaphthalene N,N-dicyclopropyl-7-ethyl-1-amino-1,2,3,4-

tetrahydronaphthalene N,N-dicyclopropyl-8-butoxy-l-amino-1,2,3,4-

tetrahydronaphthalene N-cyclopropyl-7-methoxy1-amino-l,2,3,4-

tetrahydronaphthalene N-cyclopropyl-6,7-dimethoxy-l-amino-1,2,3,4-

tetrahydronaphthalene N-cyclopropyl-7-ethyl-1-amino-1,2,3,4-

tetrahydronaphthalene N-cyclopropyl-6,7-dichloro-1-amino-1,2,3,4-

tetrahydronaphthaleneN-cyclopropyl-8-fluoro-l-amino-l,2,3,4-tetrahydronaphthaleneN-cyclopropyl-6-methoxy-7-bromo-l-amino-1,2,15,4-

tetrahydronaphthalene N-cyclopropyl-7-isobutoxy-l-amino-1,2,3,4-tetrahydronaphthalene N-methyl-N-cyclopropyl-l-amino-l,2,3,4-

tetrahydronaphthalene N-s.-butyl-N-cyclopropyll-amino-l,2, 3,4-

tetrahydronaphthalene N-ethyl-N-cyclopropyl-S-chloro-1-amino-1,2,3,4-

tetrahydronaphthalene N-propyl-N-cyclopropyl-6-chloro-l-amino-1,2,3,4-

tetrahydronaphthaleneN-methyl-N-cyclopropyl-6,8-dibromo-l-amino-1,2,3,4-

tetrahydronaphthalene N-ethyl-N-cyclopropyl-7-iodo-1-amino-1,2,3,4-

tetrahydronaphthalene N-butyl-N-cyclopropyl-S,8-di-t.-butoxy-1-amino-1,2,3,4-tetrahydronaphthaleneN-methyl-N-cyclopropyl-6-hydroxy-l-amino-l,2,3,4-

tetrahydronaphthalene N-cyclopropyl-7-hydroxy-l-amino-l,2,3,4-

tetrahydronaphthalene N-cyclopropyl-6,7-dihydroxy-1-amino-l,2,3,4-

tetrahydronaphthalene The compounds for use in the present invention inwhich Y in Formula I is ethylene are novel compounds and accordinglyform a part of this invention. These novel compounds and the othercompounds of Formula I may be made using known procedures.

Thus, for example, the compounds of Formula I may be prepared byreacting a compound of the formula:

wherein R R and Y are as defined in Formula I, with a N-substitutedformarnide of the formula:

HCONHR III wherein R represents R (other than hydrogen) or R andsubmitting the resulting formamide to an acid or alkaline hydrolysis toform an N-monosubstituted 1- aminobenzocycloalkane of the formula:

wherein R R R and Y are as defined above, (the compounds of Formula IVwherein R represents R being, of course, compounds of this invention)and thereafter, if desired (when R represents R reacting the compound ofFormula IV with a lower alkylating or cyclopropylating agent, andnecessarily (when R represents R which in turn is lower alkyl) reactingthe compound of Formula IV with a cyclopropylating agent, to produce therequired compound of Formula I in which R is lower alkyl or cyclopropyland R is cyclopropyl, the benzocycloalkanes produced by the foregoingreactions being isolated either per se or as pharmaceutically acceptablesalts thereof. Suitable lower alkylating and cyclopropylating agents foruse in the above reaction include lower alkyl and cyclopropyl halides,for example chlorides, bromides and iodides, sulphates,benzenesulphonates and p-toluenesulphonates and the alkylating reactionis advantageously carried out in an inert solvent such as ether,benzene, toluene or dioxan, and in the presence of a proton acceptor,for example an excess of the benzocycloalkane of Formula IV or anorganic base such as an alkali metal, an alkali metal amide or an alkalimetal hydride. Due to the poor reactivity of the above cyclopropylatingagents, it is preferred that, when a compound of Formula I in which R islower alkyl and R is cyclopropyl is required, the N-cyclopropyl group befirst attached to the ring and the resultant compound then loweralkylated.

The compounds of Formula IV above may also be obtained by condensing acompound of the formula:

X R1 & m Y R: V

wherein R R and Y are as defined in Formula I and X is halogen,preferably chlorine, with an amine of the formula:

R NH VI wherein R is as defined in Formula III, advantageously using anexcess of the amine or an organic base, for example pyridine, as aproton acceptor.

Alternatively the compounds of Formula IV above may be prepared byreacting a compound of Formula II, wherein R R and Y are as defined inFormula I, with an amine of Formula VI, wherein R is as defined in 4Formula III, in a suitable solvent such as benzene and eithersimultaneously or thereafter reducing the resultant l-aminoindene or1-amino-3,4-dihydronaphthalene to produce the required compound ofFormula IV, the reduction being effected with a reducing agent such aspalladium on charcoal or palladium on barium sulphate.

The foregoing method is also the method of choice for preparing thosecompounds of Formula I wherein R and R are both cyclopropyl. In thatcase the compound of Formula II is reacted with dicyclopropylamine.

Salts of the compounds of Formula I include acid addition salts andresin salts. Acid addition salts comprise pharmaceutically acceptable,non-toxic addition salts with suitable acids, such as those withinorganic acids, for example hydrochloric, hydrobromic, nitric,sulphuric or phosphoric acids, or with organic acids, such as organiccarboxylic acids, for example acetic, glycollic, maleic, tartaric,citric, o-acetyloxy-benzoic, nicotinic or isonicotinic acid, or organicsulphonic acids, for example methane sulphonic, ethane sulphonic,2-hydroxyetl1ane sulphonic, p-toluene sulphonic or naphthalene2-sulphonic acid.

A resulting acid addition salt may be converted into the free compoundaccording to known methods, for example, by treating it with a base suchas with a metal hydroxide, for example an alkali metal or alkaline earthmetal hydroxide, for example lithium hydroxide, sodium hydroxide,potassium hydroxide or calcium hydroxide; a metal carbonate, such as analkali metal or an alkaline earth metal carbonate or hydrogen carbonate,for example sodium, potassium or calcium carbonate or hydrogencarbonate; ammonia; with a hydroxyl ion exchange preparation, or withany other suitable reagent.

A resulting acid addition salt may also be converted into another acidaddition salt according to known methods; for example, a salt with aninorganic acid may be treated with a metal salt, for example sodium,barium or silver salt, of an acid in a suitable diluent, in which aresulting inorganic salt is insoluble and is thus removed from thereaction medium. An acid addition salt may also be converted intoanother acid addition salt by treatment with an anion exchangepreparation.

A free compound may be converted into an acid addition salt according toknown methods, for example, by reacting the base, preferably a solutionthereof in a solvent or solvent mixture, with the appropriate acid or asolution thereof, or with an anion exchange preparation and isolatingthe desired salt, which may be obtained in the form of a hydrate or maycontain solvent of crystallization.

Resin salts of the compounds of Formula I, that is to say a substance inwhich the base is ionically bonded to an ion exchange material, may beobtained by contacting a cation exchange material with a solution in aninert, preferably polar, solvent of the base until the desired degree ofsaturation, usually substantially complete saturation, of the exchangematerial with the base has taken place. Suitable cationic exchangeresins for this purpose are Zeocarb 225H, Dowex SOW-XS, Amberlite IR (H)and Amberlite IRC 50(H).

As previously mentioned, the compounds of Formula I have been found tohave a hypotensive activity and accordingly the present inventionprovides a method of lowering blood pressure in the animal, includinghuman, body which method comprises administering in a sufficientnon-toxic dose a compound of Formula I or a pharmaceutically acceptablesalt thereof.

It will be appreciated that for medicinal use, the compounds of theinvention can be made up, in accordance with pharmaceutical techniqueswell known per se, into pharmaceutical compositions comprising as anessential active ingredient a derivative of Formula I or apharmaceutically acceptable acid addition salt thereof and apharmaceutical carrier for the active ingredient. The pharmaceuticalcarrier may be an orally ingestible c0ntainer for the activeingredients, for example a hard or soft gelatin capsule, or the carriermay be a pharmaceutical diluent or excipient which is in admixture withthe active ingredient, for example starch, lactose, mannitol, sorbitol,calcium phosphate, talc magnesium stearatc, stearic acid,ethylcellulose, oil of theobroma, glycerin, or water, or a preservativesuch as for example methyl p-hydroxybenzoate. The composition may be ina form suitable for oral, parenteral or rectal administration and maytherefore take the form of, for example a sterile solution or suspensionin water or other liquids for parenteral administration or a suppositoryfor rectal administration. However, for clinical practice the compoundof the invention will preferably be administered by the oral route andhence the preferred compositions will be made up in a form suitable fororal ingestion, for example solutions, suspensions, emulsions, elixirs,syrups, powders or tablets.

For clinical use, the compositions are advantageously made up in adosage unit form adapted for the desired mode of administration. Thusfor oral administration, the dosage unit may take the form of, forexample, a tablet, pill, sachet, cachet, packaged powder or a hard orsoft gelatin capsule which may enclose a liquid, semi-liquid or solidcomposition of the pure active ingredient. For administration byinjection, the dosage unit may take the form of a container such as anampoule containing either an injectable solution or a composition fromwhich such a solution may be prepared. The quantity of active ingredientin each dosage unit will be such that one or more, and conveniently nomore than 2 or 3, units are required for each therapeuticadministration. For example, the dosage unit for use in humans maycontain from 1 to 150, advantageously 5 to 100 mg. of the activeingredient. The dosage units may be administered from two to four timesdaily depending on the condition of the patient. The number of dosagesper day and/or the size of each dosage may be reduced during maintenancetherepy, i.e. after the initial high blood pressure has been lowered toan acceptable level.

The following examples illustrate the preparation of compounds andcompositions in accordance with the invention.

Example 1 Tablets each having the following composition were prepared asdescribed below:

Ethylcellulose N.100 is a. commercially available ethoxylated cellulosehaving an ethoxyl content of 47.5 to 49.0%. A 5% w./w. solution in 80parts toluene/20 parts ethanol has as viscosity of 80 to 105 cp. at 25C.

The N-cyclopropyl 1 aminoindane hydrochloride, lactose and a proportionof the starch (20 mg./tablet) were passed through a No. 44 (B.S.S.) meshsieve and mixed together. The mixed powders were massed with a 5% w./ W.solution of ethylcellulose in isopropyl alcohol and the mass granulatedthrough a No. 12 (B.S.S.) mesh sieve. The granules were dried at 40 C.and passed through a No. 16 (B.S.S.) mesh sieve. Finally the talc,

6 Example 2 Tablets each having the following composition were preparedas described below:

N-cyclopropyl 5 methoxy-l-aminoindane hydrochloride Lactose 248 Maizestarch (dried) 70 Ethylcellulose N S Talc 20 Magnesium stearate 4 TheN-cyc lopropyl-S-methoxy 1 aminoindane hydrochloride, lactose and aproportion of the starch (40 mg./ tablet) were passed through a No. 44(B.S.S.) mesh sieve and mixed together. The mixed powders were massedwith a 5% w./w. solution of ethylcellulose in isopropyl alcohol and themass granulated through a No. 12 (B.S.S.) mesh sieve. The granules weredried at 40 C. and then passed through a No. 16 (B.S.S.) mesh sieve.Finally the talc, magnesium stearate and the balance of the starch (allpassed through a No. 60 (B.S.S.) mesh sieve) were added to the granulesand the mixture compressed into tablets each weighting 400 mg.

Example 3 Capsules each having the following composition were made up asdescribed below:

Mg. N-cyclopropyl-l-aminoindane hydrochloride l0 Lactose TheN-cyclopropyl-l-aminoindane hydrochloride and lactose were passedthrough a No. 44 (B.S.S.) mesh sieve and well mixed together. The mixedpowders were filled into hard gelatin capsules of suitable size so thateach contained mg. of the mixture.

Example 4 Capsules each having the following composition were made up asdescribed below:

Mg. N,N-dicyclopropyl-l-aminoindane hydrochloride 50 Lactose 80 Thisformulation was made up in the same way as in Example 3 and filled intohard gelatin capsules so that each contained 130 mg. of the mixedpowder.

Example 5 Suppositories each having the following compositions were madeup as described below:

N-cyclopropyl-l-amino 1,2,3,4 tetrahydronaphthalene hydrochloride-10 mg.Oil of theobroma-0.995 g.

Example 6 Suppositories each having the following composition were madeup as described below:

N-cyclopropyl 6,7 dimethoxy 1 amino 1,2,3,4-

tetrahydronaphthalene hydrochloride-50 mg. Oil of theobroma-0.75 g.

The formulation was made up in the same way as described in Example 5and each suppository contained 50 mg. of Ncyclopropyl-6,7-dimethoxy-l-amino-1,2,3,4- tetrahydronaphthalenehydrochloride.

Example 7 A sterile powder for the preparation of an injection solutionof N cyclopropyl-N-methyl 1 aminoindane hydrochloride was prepared asdescribed below:

A( i) The N-cyclopropyl-N-methyl-l-aminoindane hydrochloride wassterilised by contact with ethylene oxide and 5 mg. quantitiestransferred aseptically to the sterile final containers which were thenaseptically sealed. When required for use this sterile powder may bedissolved in 1 ml. or more of sterile normal saline solution forinjection.

(ii) The N-cyclopropyl-N-methyl-1aminoindane hydrochloride wassterilised by contact with ethylene oxide and 100 mg. quantitiestransferred aseptically to the sterile final containers which were thenaseptically sealed. When required for use this sterile powder may bedissolved in 1 ml. or more of sterile normal saline solution forinjection.

B(i) The N-cyclopropyl-N-methyl-l-aminoindane hydrochloride wasdissolved in distilled water so that the resultant solution containedmg./ml. This solution was then filtered through a bacteria proof filterand transferred aseptically into the final sterile containers which werethen freeze dried under aseptic conditions. This sterile freeze driedpowder may then be dissolved in 1 ml. or more of normal saline solutionfor injection.

(ii) The N-cyclopropyl-N-methyl-l-aminoindane hydrochloride wasdissolved in distilled water so that the resultant solution contained100 mg/ml. This solution was filtered through a bacteria proof filterand transferred aseptically into the final sterile containers which werethen freeze dried under aseptic conditions. This sterile freeze driedpower may then be dissolved in 1 ml. or more of normal saline solutionfor injection.

Example 8 Injection solutions N cyclopropyl 1 aminoindane hydrochloridewere prepared as described below:

(i) The N-cyclopropyl-l-aminoindane hydrochloride was dissolved innormal saline for injection so that the resultant solution contained 5mg./ml. This solution was then filtered through a bacteria proof filterand transferred aseptically to the final sterile containers.

(ii) The N-cyclopropyl-l-aminoindane hydrochloride was dissolved innormal saline for injection so that the resultant solution contained 10mg./ml. This solution was filtered through a bacteria proof filter andtransferred aseptically to the final sterile containers.

(iii) The N-cyclopropyl l aminoindane hydrochlorine was dissolved innormal saline solution for injection so that the resultant solutioncontained 50 mg./ml. This solution was then filtered through a bacteriaproof filter and transferred aseptically to the final sterilecontainers.

Example 9 A syrup was prepared as described below:

N cyclopropyl 6 t.butoxy 1 amino 1,2,3,4 tetrahydronaphthalenehydrochloride1.0 g.

Glycerin-50.0 ml.

Liquid invert sugar-500.0 ml.

Methyl p-hydroxybenzoate--1.0 g.

Propyl p-hydroxybenzoate0.4 g.

Propylene glycol10.0 ml.

Distilled water qs. to 1.0 litre.

The N cyclopropyl 6 t.butoxy 1 amino-1,2,3,4- tetrahydronaphthalene wasdissolved in 300 ml. of dis tilled water and the liquid invert sugaradded to this solution.

Both the methyl and propyl p-hydroxybenzoates were dissolved in thepropylene glycol with the aid of heat and the resultant solution dilutedwith the glycerin. This solution was then added to the prepared solutionof the tetrahydronaphthalene hydrochloride and further distilled wateradded to give a final volume of 1 litre.

Each 5 ml. of prepared syrup contains 5 mg. of the active ingredient.

Example 10 A syrup containing N cyclopropyl 1 aminoindane hydrochloridewas prepared as described below: N-cyclopropyl-l-aminoindanehydrochloride10.0 g. Glycerin-50.0 ml.

Liquid invert sugar500.0 ml. Methyl p-hydroxybenzoatel.0 g. Propylp-hydroxybenzoate-0.4 g. Propylene glycol-l0.0 ml. Distilled water qs.to 1.0 litre.

This syrup was made up in the manner described in Example 9. Each 5 ml.of the prepared syrup contains 50 mg. of the active ingredient.

It will be appreciated that in Examples 1 to 10, the active compoundspecified may be replaced in Whole or in part by other compounds of theinvention having the necessary pharmacological activity and that otherpharmaceutically acceptable salts may be employed in place of thehydrochloride salts.

EXAMPLE 1 1 A mixture of l-chloroindane (13.42 g.; .088 mole) andcyclopropylamine (10 g.; 0.176 mole) was heated on a steam bath for 4 /2hours, during which time two layers formed, the lower one solidifying oncooling. Petroleum ether, B.P. 4060 C. ml.) was added, the solidcyclopropylyarnine hydrochloride filtered off, and the petroleum etherevaporated off from the filtrate. The resulting residue was dissolved inether (30 ml.) and then extracted with dilute hydrochloric acid (5 N).At this stage a white crystalline precipitate was formed which wasfiltered off and recrystallised from isopropanol to obtainN-cyclopropyl-l-arninoindane hydrochloride, M.P. l89-190 C. (4.8 g.).The separated acid layer was made alkaline with 5 N sodium hydroxide andthe basic oil ether extracted. Addition of ethereal hydrogen chloride tothe dried ether extract precipitated N-cyclopropyl-laminoindanehydrochloride as colourless crystals, M.P. 181-182 C. afterrecrystallisation from isopropanol (2.8 g). Total yield 7.6 g.

The above N-cyclopropyl-l-aminoindane hydrochloride (5 g.) was dissolvedin water (50 ml.) and the solution treated with 5 N sodium hydroxide (5ml.). The resulting cloudy mixture was extracted with ether, the extractdried and distilled to give N-cyclopropyl-l-arninoindane,

B.P. 183 C./2O mm. or 6566 C./0.05 mm. (3.6 g.).

EXAMPLE 12 A mixture of N-cyclopropyl-l-aminoindane (8.65 g,; 0.05mole), ethyl iodide (4 g.; 0.025 mole) and methyl cyanide was refluxedfor 12 hours. The methyl cyanide was evaporated off under reducedpressure and the residue warmed with anhydrous ether. The solidremaining undissolved was filtered off and the filtrate distilled togive N-ethyl-N-cyclopropyl-l-aminoindane, B.P. 6265 C./O.1 mm.

EXAMPLE 13 A mixture of a-tetralone (14.6 g.; 0.1 mole),cyclopropylamine (5.7 g.; 0.1 mole), dry benzene ml.) andcyclopropylamine p-toluene sulphonate (0.05 g.) was refluxed for 48hours in a Soxhlet apparatus using a thimble containing powdered calciumoxide. The benzene was distilled off and the residue distilled to giveN-cyclopropyl-1-amino-3,4-dihydronaphthalene, B.P. 103-5 C./ 0.6 mm.

A solution of N-cyclopropyl-l-arnino-3,4-dihydronaphthalene (7 g.; 0.038mole) in a mixture of glacial acetic acid (5 ml.) and asbolute ethanol(50 ml.) was hydrogenated at room temperature and atmospheric pressureusing palladium on charcoal 0.29 g.) as catalyst. After 0.038 mole ofhydrogen had been absorbed, the solution was filtered, evaporated underreduced pressure, the residual oil diluted with water and the mixturemade alkaline by the addition of dilute sodium hydroxide.N-cyclopropyl-l-amino 1,2,3,4 tetrahydronaphthalene separated as an oilylayer and was extracted into ether. The ether extract was dried,concentrated and then treated with ethereal hydrogen chloride. Theprecipitated hydrochloride was filtered OE and crystallised fromisopranol to give N-cyclopropyl-l-amino-1,2,3,4-tetrahydronaphthalenehydrochloride, M.P. 171-172 C.

EXAMPLE 14 A mixture of S-methoxy-l-indanone (6.1 g; 0.038 mole),cyclopropylamine (2.17 g.; 0.038 mole), cyclopropylamine p-toluenesulphonate (0.05 g.), abbsolute ethanol (110 ml.), glacial acetic acid(2 ml.) and 5% palladium ou barium sulphate (1 g.) was reacted at roomtemperature and atmospheric pressure. The warmed mixture was filtered,acidified with dilute hydrochloric acid, the ethanol evaporated off andthe residue dissolved in water. The solution was extracted with ether,the aqueous layer separated and basified with dilute sodium hydroxide.The oily layer was isolated by ether extraction. Distillation of theether extract yielded N-cyclopropyl-S- methoxy-l-aminoindane, B.P.102-106 C./0.3 mm. The base was converted to its hydrochloride bytreatment with ethereal hydrogen chloride. After crystallisation frommethanol it had a M.P. 172173 C.

EXAMPLE 15 A mixture of 5,6-dimethoxy-1-indanone (19 g.; 0.099 mole),cyclopropylamine (6.7 g.; 0.1 mole), cyclopropylaminep-toluenesulphonate (0.1 g), absolute ethanol (150 ml.), glacial aceticacid (6 ml.) and 5% palladium on barium sulphate (2 g.) was reacted atroom temperature and atrospheric pressure. The mixture was then workedup as in Example 14 to give N-cyclopropyl-5,6- dimethoxy-l-aminoindane,B.P. 186-190 C./ 15 mm. Treatment of the base with ethereal hydrogenchloride and crystallisation of the solid from ethanol gaveN-cyclopropyl-5,6-dimethoxy-l-aminoindane hydrochloride, M.P. 193 C.

EXAMPLE 16 6-methoxy-a-tetralone (19.1 g.; 0.11 mole) was treated withcyclopropylamine (8.7 g.; 0.13 mole) as in Example 13 to giveN-cyclopropyl-6-methoxy-1-amino-3,4-dihydro- 10 naphthalene B.P. 140C./0.1 mm. (hydrochloride M.P. 19l120 C.). This was then hydogenated asin Example 13 to give the N-cyclopropyl-6-methoxy-1-amino-1,2,3,4-tetrahydronaphthalene, B.P. 118 C./1

Having regard to the foregoing disclosure, the following is claimed asthe inventive and patentable embodiments thereof:

1. A compound of the formula:

wherein R and R which may be same or different, are hydrogen, methyl,ethyl, halogen, hydroxy or lower a1- koxy; R is hydrogen, lower alkyl orcyclopropyl; R is cyclopropyl; or a pharmaceutically acceptable saltthereof.

2. A compound in accordance with claim 1 in which R R and R arehydrogen; and pharmaceutically acceptable salts thereof.

3. A compound in accordance with claim 1 in which R and R are hydrogenand R is a 6-methoxy group; and pharmaceutically acceptable saltsthereof.

4. A compound in accordance with claim 1 in which R is 6-methoxy, R is7-methoxy, and R is hydrogen; and pharmaceutically acceptable saltsthereof.

5. A compound in accordance with claim 1 in which R and R are hydrogen,and R is 6-tertiary-butoxy; and pharmaceutically acceptable saltsthereof.

Ames et al., J. Chem. Soc., London, pp. 2636-41, April 1965.

HENRY R. JILES, Primary Examiner A. L. ROTMAN, Assistant Examiner U.S.Cl. X.R.

216 016 Cip Cont 9 23 um'ricn STA'IES 'lA'll'lN'l OFFICE (HQHTIFICATE OFCORRECTION 3 534, 055 Dated October 13, 1970 Maurice Ward Gittos, JohnWilliam James, and Inventor(s) Leslie Frederick Wiggins Patent No.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

I- In Column 1, line 5, after the name "James" there should be a comma.Column 2, between lines '10 and 11, the following line has been omitted-N-cyclopropy1-6-methoxy-1-aminoindane--; Column 5, line 5, after "talc"there should be a. comma line 25, "of" should be --or--; in the lastline of the footnote below line 55 "as" should be a Column 6, line 24,"weighting" should be --weighing-; line 71, "0.75" should be 0.975Column 7, line 37, after "solutions" insert --of--; Column 9, line 17,"abbsolute" should be -absolute--; Column 10, Claim 3, line 2, the first"R" should be R SELLED QSEAL) Atteat:

mm n. 2 Edward m Oumissiom of Pamfl Attesting Officar

